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Persistence of Rilpivirine Following Single Dose of Long-Acting Injection Ian McGowan MD DPhil FRCP Professor of Medicine, University of Pittsburgh for the MWRI-01 Team
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Disclosure I have no financial relationships with a commercial entity producing, marketing, reselling or distributing healthcare related products and/or services.
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Antiretroviral Persistence Long acting (LA) injectable antiretrovirals (ARV) are being developed for both treatment and prevention indications The extended half-life associated with LA- ARV is poorly characterized but may increase the risk of ARV resistance in individuals who seroconvert after exposure to LA PrEP
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The Pharmacokinetic (PK) Tail Female participant receiving a single 1200 mg dose of rilpivirine (RPV) McGowan I et al. HIVR4P 2014
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Resistance after Single 300mg Dose of RPV LA Penrose K et al. JID 2016 Time after injection (days)
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Methods
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MWRI-01 Study A Phase 1 safety, acceptability, PK/PD evaluation of RPV LA (TMC278) Single dose phase Men and women randomized to receive 600 mg or 1200 mg of TMC278 LA Multiple dose phase Men and women received 1200 mg of TMC278 LA
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Primary Objectives Primary objective To evaluate the safety and acceptability of RPV LA given as an intramuscular injection Primary endpoints Grade 2 or higher clinical and laboratory adverse events The proportion of participants who would consider using RPV LA for HIV prevention in the future
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Secondary Objectives Secondary objectives To determine the plasma, cervical, vaginal, and rectal tissue/secretion PK following single and multiple IM injections of RPV LA Secondary endpoints RPV concentrations in plasma, cervical, vaginal, and rectal tissue/secretions
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MWRI-01 Design ScreenBaseline+1 month +2 month +3 month +4 month +5 month +6 month N = 5 N = 4 ♀ ♂ 1200 mg 600 mg 1200 mg 600 mg 1A (N=12) 2A (N=12) 1B (N=6) 2A (N=6) 1200 mg 3A (N=8) 3A (N=4)
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PK Analysis (1) RPV concentrations in all matrices were quantified by validated high-pressure liquid chromatography-mass spectrometry Matrix lower limit of quantification (LLOQ) Plasma: 0.5 ng/ml Fluids: 0.025 ng/sample Tissue: 0.05 ng/sample Else LJ et al. Bioanalysis. 2014
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PK Analysis (2) Two blanks (extracted drug-free plasma) were included after the upper limit of quantification (400 ng/ml) and after the MQC/HQC The % carryover after a single blank sample was <20% of the assay LLQ (0.5 ng/ml)
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Results
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Demographics Baseline samples were available from 9 participants 1200 mg: 5 females and 2 males 600 mg: 2 males
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Persistence of RPV RPV was detectable in 7/7 (100%) of plasma samples collected a mean of 541 days after single dose exposure to 1200 mg of RPV LA RPV was also detected in endocervical and vaginal fluid No RPV was found in cervical, vaginal, or rectal tissue or cervicovaginal lavage samples
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Baseline PK 4.1 ± 2.46.1 ± 4.113.2 ± 10.9
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Time from RPV LA Exposure All Samples1200mg Samples
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Time from RPV LA Exposure All Samples1200mg Samples
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Conclusions Quantifiable RPV was found in plasma and female genital tract fluids > 18 months after single dose administration of RPV LA (Mean plasma level 4.1 ng/mL) Protein-adjusted RPV EC 90 is 12 ng/mL Further characterization of LA PrEP extended PK profile will be critical to better inform management of the PK tail to avoid the potential for ARV resistance
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Acknowledgements University of Pittsburgh Clinical and Stats Support Ross Cranston Beatrice Chen Sharon Achilles Ron Stall Patty Peters Carol Oriss Carly Mowry Carol Mitchell Jonathan Baker Stacey Edick Kaleab Abebe Cindy Jacobson University of Pittsburgh Lab Support Charlene Dezzutti Kathy Duffill Aaron Siegel Jarret Engstrom Alexyi Nikorov University of Pittsburgh Recruitment and Project Management Support Kathy McCarthy University of Liverpool David Back Saye Khoo Laura Else Deidre Egan Janssen R & D Peter Williams Marita Stevens Joseph Mrus Alpha StatConsult LLC Nicola Richardson-Harman Bill & Melinda Gates Foundation Lut Van Damme
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Funding for the MWRI-01 Study
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